The farnesoid X receptor (FXR) is a nuclear hormone receptor that regulates gene expression in response to bile acids. FXR is important in the metabolism of bile acid, cholesterol, and lipoproteins. FXR agonists may be used in treating atherosclerosis, diabetes and cholestatic disease. Chenodeoxycholic acid (CDCA, FIG. 1) is a primary bile acid and among the most potent natural ligand of FXR with EC50 values around 50 μM. Other bile acids, such as lithocholic acid, cholic acid (CA, FIG. 1) and deoxycholic acid (DCA, FIG. 1) also activate FXR, while ursodeoxycholic acid is inactive. The most potent synthetic non-steroidal FXR agonist, GW4064, has been identified through the use of high-throughput screening and combinatorial chemistry. Recent studies indicate that GW4064 activates FXR, increases HDL-cholesterol and reduces plasma triglycerides in vivo. However, GW4064 has very poor pharmacokinetic properties and is not useful clinically.
In a different approach, synthetic steroidal 6-ECDCA has recently been identified by traditional medicinal chemistry methods and found to be more potent with EC50 values around 100 nM compared to the parent CDCA derivative and with improved pharmacokinetic properties relative to GW4064 (FIG. 1). Therefore, 6-ECDCA is a prime candidate for use in pharmacological therapy and as a tool to study the function of FXR. In existing methods for the preparation of 6-ECDCA, 7-keto-lithocholic acid, a very expensive starting material, is protected at the 3 position. The product is reacted with ethyl bromide under LDA to obtain the ethylating intermediate, followed by treatment with methanolic HCl under refluxed condition gave a methyl ester. Finally, selective reduction of methyl ester with sodium borohydride and subsequent hydrolysis of the methyl ester with NaOH in the methanol under refluxed condition to give 6-ECDCA in 3% yield for the synthesis of 6-ECDCA. Given the great promise of 6-ECDCA of a research tool and therapeutic molecule, a more efficient and less expensive methodology for the synthesis of this compound is needed. An efficient and economical methodology for the synthesis of similarly alkylated bile acid derivatives is also desired.